TET2 – Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by elevated pulmonary vascular resistance and right‐heart failure. While germline mutations in BMPR2 and other signaling genes explain <25% of idiopathic PAH, emerging data implicate epigenetic dysregulation in disease pathogenesis, with TET2—a key 5-methylcytosine dioxygenase—identified as a novel candidate PAH gene (PMID:32192357).

Rare variant association testing in 1,832 unrelated European PAH patients versus 7,509 non-Finnish European controls revealed enrichment of predicted deleterious TET2 variants (9/1832 vs 6/7509; RR=6, P=0.00067)(PMID:32192357). Across the full PAH Biobank cohort (n=2,572), 0.39% of patients (10/2572) harbored 12 TET2 mutations—75% germline and 25% somatic—with no co-occurrence of other known PAH gene mutations (PMID:32192357). An independent Japanese cohort identified a heterozygous missense variant, c.3116C>T (p.Ser1039Leu), in 3 of 145 patients (2.1%; allele frequency 0.15% in gnomAD)(PMID:35495859).

The variant spectrum comprises predominantly heterozygous missense substitutions, some predicted to impair the catalytic oxidation of 5-methylcytosine. All carriers exhibited late-onset PAH (mean age 71 vs 48 years; P<0.0001) with reduced responsiveness to vasodilators, lower pulmonary vascular resistance (5.2 ± 3.1 vs 10.5 ± 7.0 Wood units; P=0.02), and elevated inflammatory markers, including interleukin-1β (PMID:32192357).

Mechanistic studies demonstrate that TET2 expression is decreased in >86% of PAH patients irrespective of mutation status and does not correlate with age (PMID:32192357). Hematopoietic Tet2-knockout mice develop spontaneous PAH with adverse pulmonary vascular remodeling and inflammation, mirroring human disease; long-term anti–interleukin-1β therapy regresses PAH in this model (PMID:32192357).

These findings support a loss-of-function mechanism for TET2 in PAH, whereby haploinsufficiency leads to aberrant DNA methylation, heightened inflammation, and vascular remodeling. Although rare (0.39% of cases), TET2 mutations identify a clinically distinct PAH subset marked by older age at onset and pronounced inflammatory phenotype.

Key Take-home: TET2 mutations define a rare, late-onset, inflammation-driven form of PAH with potential biomarker and therapeutic implications, including IL-1β blockade.

References

• Circulation • 2020 • Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension PMID:32192357
• [Title unavailable] • [Year unavailable] • Frequency of a germline TET2 variant in Japanese PAH patients PMID:35495859

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